Substantial evidence has conclusively demonstrated that aspirin reduces risk of colorectal neoplasia. Nonetheless, the U.S. Preventive Services Task Force recommended against routine of use of aspirin to prevent colorectal cancer (CRC) largely due to uncertainty regarding its mode of action and concerns about the dose-related risk of gastrointestinal bleeding (GIB). In the current funding period, we made several important, high-impact contributions to address these issues and advance the field of chemoprevention. First, aspirin inhibits neoplasia through multiple interrelated biological mechanisms, including prostaglandin synthesis (prostaglandin-endoperoxidase synthase-2 [PTGS-2 or COX-2]); prostaglandin catabolism (15-hydroxyprostaglandin dehydrogenase [15-PGDH]); chronic inflammation (macrophage inhibitory cytokine-1 [MIC-1/GDF15]); and the TCF7L2/TCF4 transcription factor, a component of Wnt signaling at the 8q24 CRC risk locus that is a known enhancer to MYC. Second, aspirin chemoprevention may be tailored according to biomarkers of prostaglandin tone, such as urinary prostaglandin metabolites (PGE-M). Third, we and others have shown that use of aspirin, including low, anti-platelet doses, is associated with a lower risk of death from CRC as well as multiple cancers. Last, aspirin improves survival among CRC patients, particularly those with somatic PIK3CA mutations. Nonetheless, there remains a limited understanding of aspirin's overall risk- benefit profile after incorporating other cancer outcomes and cardiovascular disease (CVD) for which aspirin has established benefit. The field is now at crucial juncture to translate these findings into the clinic. There remains a high unmet need to 1) define the optimal dose, timing, and duration of aspirin use in relation to absolute ris of cancer, CVD, and GIB in the overall population as well as according to specific subgroups (e.g. sex or comorbidities); 2) identify individuals most likely to benefit and advance mechanistic understanding of aspirin's anti-cancer effect. Our central hypothesis is that aspirin, by reducing risk of multiple cancers and CVD, has a favorable risk-benefit profile for most individuals and influences several neoplastic pathways which can be exploited as biomarkers of chemopreventive efficacy. In this competing renewal, we will test this hypothesis through first-of-its kind human studies that 1) assess aspirin, at a range of dose, timing, and duration of use within sufficiently large and well-characterized cohorts to provide robust estimates of risk-benefit; 2) determine if randomized aspirin treatment, at anti-platelet (81 mg/d) or standard doses (325 mg/d), influences specific mechanistic biomarkers of colorectal carcinogenesis to advance correlation to causality. Because these data are critical to inform ongoing efforts to formulate recommendations for aspirin chemoprevention, our study has the potential for transformative public health impact.